Publicaciones

Ipsilesional Hippocampal GABA Is Elevated and Correlates With Cognitive Impairment and Maladaptive Neurogenesis After Cortical Stroke in Mice

Torres-López C, Cuartero MI, García-Culebras A et al. Stroke. 2023 Oct;54(10):2652-2665. doi: 10.1161/STROKEAHA.123.043516. Epub 2023 Sep 11. PMID: 37694402

https://pubmed.ncbi.nlm.nih.gov/37694402/

Abstract: 

BACKGROUND: Cognitive dysfunction is a frequent stroke sequela, but its pathogenesis and treatment remain unresolved. Involvement of aberrant hippocampal neurogenesis and maladaptive circuitry remodeling has been proposed, but their mechanisms are unknown. Our aim was to evaluate potential underlying molecular/cellular events implicated.
METHODS: Stroke was induced by permanent occlusion of the middle cerebral artery occlusion in 2-month-old C57BL/6 male mice. Hippocampal metabolites/neurotransmitters were analyzed longitudinally by in vivo magnetic resonance spectroscopy. Cognitive function was evaluated with the contextual fear conditioning test. Microglia, astrocytes, neuroblasts, interneurons, γ-aminobutyric acid (GABA), and c-fos were analyzed by immunofluorescence.
RESULTS: Approximately 50% of mice exhibited progressive post–middle cerebral artery occlusion cognitive impairment. Notably, immature hippocampal neurons in the impaired group displayed more severe aberrant phenotypes than those from the nonimpaired group. Using magnetic resonance spectroscopy, significant bilateral changes in hippocampal metabolites, such as myo-inositol or N-acetylaspartic acid, were found that correlated, respectively, with numbers of glia and immature neuroblasts in the ischemic group. Importantly, some metabolites were specifically altered in the ipsilateral hippocampus suggesting its involvement in aberrant hippocampal neurogenesis and remodeling processes. Specifically, middle cerebral artery occlusion animals with higher hippocampal GABA levels displayed worse cognitive outcome. Implication of GABA in this setting was supported by the amelioration of ischemia-induced memory deficits and aberrant hippocampal neurogenesis after blocking pharmacologically GABAergic neurotransmission, an intervention which was ineffective when neurogenesis was inhibited. These data suggest that GABA exerts its detrimental effect, at least partly, by affecting morphology and
integration of newborn neurons into the hippocampal circuits.
CONCLUSIONS: Hippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for poststroke cognitive impairment.

Funding: This work was supported by grants from Spanish Ministry of Science and Innovation (MCIN) PID2019-106581RB-I00 (Dr Moro), from Leducq Foundation for Cardiovascular Research TNE-19CVD01 (Drs Moro and Buckwalter) and TNE- 21CVD04 (Drs Moro and Lizasoain), from Instituto de Salud Carlos III (ISCIII) and co-financed by the European Development Regional Fund “A Way to Achieve Europe” PI20/00535 and RICORS (Redes de Investigación Cooperativa Orientadas a Resultados en Salud)-ICTUS RD21/0006/0001 (Dr Lizasoain) and from American Heart Association and Paul Allen Frontiers group 19PABHI34580007 (Dr Buckwalter). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the ISCIII, the MCIN, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). The microscopy
experiments were performed in the Unidad de Microscopía e Imagen Dinámica, CNIC, ICTS-ReDib (Infraestructura Científica y técnica Singular – Red Distribuida de Imagen Biomédica), cofunded by MCIN/AEI (Agencia Estatal de Investigación)/ 10.13039/501100011033 and FEDER “Una manera de hacer Europa” (no. ICTS-2018-04-CNIC-16). Part of the research work included in this publication has been performed in the ICTS-ReDib infrastructure BioImaC (MCIN).

Cerebroprotective Effect of 17β-Estradiol Replacement Therapy in Ovariectomy-Induced Post-Menopausal Rats Subjected to Ischemic Stroke: Role of MAPK/ERK1/2 Pathway and PI3K-Independent Akt Activation

Burguete MC, Jover-Mengual T, Castelló-Ruiz M et al. Int J Mol Sci. 2023 Sep 19;24(18):14303. doi: 10.3390/ijms241814303. PMID: 37762606

https://pubmed.ncbi.nlm.nih.gov/37762606/

Abstract: Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17β-estradiol (E2) is neuroprotective against stroke in both male and female rodents. However, the molecular mechanisms by which E2 intervenes in ischemia-induced cell death, revealing these sex differences, remain unclear. The
present study was aimed to determine, in female rats, the molecular mechanisms of two well-known pro-survival signaling pathways, MAPK/ERK1/2 and PI3K/Akt, that mediate E2 neuroprotection in response to acute ischemic stroke. E2 pretreatment reduced brain damage and attenuated apoptotic cell death in ovariectomized female rats after an ischemic insult. Moreover, E2 decreased phosphorylation of ERK1/2 and prevented ischemia/reperfusion-induced dephosphorylation of both Akt and the pro-apoptotic protein, BAD. However, MAPK/ERK1/2 inhibitor PD98059, but not the PI3K inhibitor LY294002, attenuated E2 neuroprotection. Thus, these results suggested that E2 pretreatment in ovariectomized female rats modulates MAPK/ERK1/2 and activates Akt independently of PI3K to promote cerebroprotection in ischemic stroke. A better understanding of the mechanisms and the influence of E2 in the female sex paves the way for the design of future successful hormone replacement therapies.

Funding: This research was funded by AP-046/11 and AP-118/10 from Conselleria de Sanitat. Generalitat Valenciana; GVPRE/2008/196 from Conselleria de Educación de la Generalitat Valenciana, Spain to T.J-M.; UV-INV-AE19-1210265 from Universitat de València, Spain to M.C.B.; and RD16/0019/0008 and RD21/0006/0014 from Instituto de Salud Carlos III, Spain, to J.B.S.